There are two investigations in this project, both of which utilize chromosome variations: (1) To map genes on human chromosomes (a) by pedigree analysis methods and (b) by gene dosage effects. To accomplish (a) studies of families with heritable chromosome rearrangements are necessary. Loci to be linked to the identifiable chromosomes include 31 blood group, red cell enzyme, serum protein markers, the HLA system, and selected autosomal dominant and recessive genetic traits. Evidence for or against dependent segregation of a cytogenetic abnormality and a locus for a marker is obtained by lod score analysis utilizing the computer program developed for family studies by Ott. For (b) deletion and trisomy mapping studies utilize chromosomally unbalanced subjects and their parents; evidence for loss or gain of an allele and/or gene dosage effect is sought. (2) Investigation of autosomal non-disjunction and other de novo chromosome aberrations to determine the parental origin of the abnormality, when the involved chromosome is heteromorphic, and to determine possible causative factors. For example, the frequency of variants of chromosome 21 is such that in most cases, homologue identification is possible. These differences are heritable, thus the parent contributing two chromosomes 21 to the Down's offspring is determined. With known parental origin, suggested causes (segregation are definitively tested and compared to a control group.